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Abstract:

The blockade of adenosine A2A receptors (A2AR) affords a
robust neuroprotection in different noxious brain conditions.
However, the mechanisms underlying this general neuroprotection
are unknown. One possible mechanism could be
the control of neuroinflammation that is associated with brain
damage, especially because A2AR efficiently control peripheral
inflammation. Thus, we tested if the intracerebroventricular
injection of a selective A2AR antagonist (SCH58261)
would attenuate the changes in the hippocampus triggered
by intraperitoneal administration of lipopolysaccharide (LPS)
that induces neuroinflammation through microglia activation.
LPS administration triggers an increase in inflammatory
mediators like interleukin-1b that causes biochemical changes
(p38 and c-jun N-terminal kinase phosphorylation and
caspase 3 activation) contributing to neuronal dysfunction
typified by decreased long-term potentiation, a form of synaptic
plasticity. Long-term potentiation, measured 30 min
after the tetanus, was significantly lower in LPS-treated rats
compared with control-treated rats, while SCH58261 attenuated
the LPS-induced change. The LPS-induced increases in
phosphorylation of c-jun N-terminal kinase and p38 and
activation of caspase 3 were also prevented by SCH58261.
Significantly, SCH58261 also prevented the LPS-induced
recruitment of activated microglial cells and the increase in
interleukin-1b concentration in the hippocampus, indicating
that A2AR activation is a pivotal step in mediating the
neuroinflammation triggered by LPS. These results indicate
that A2AR antagonists prevent neuroinflammation and
support the hypothesis that this mechanism might contribute
for the ability of A2AR antagonists to control different
neurodegenerative diseases known to involve neuroinflammation.